The stability of an active pharmaceutical compound during storage over a variety of conditions is a generally of concern during development of a formulation for the compound. This aspect is especially relevant for liquid formulations of compounds which are sensitive and/or prone to decomposition via oxidation pathways. It is becoming even more relevant today as countries with hot and moderately humid climate (i.e. ICH zone IVb countries) are becoming increasingly important to pharmaceutical companies so that new drug formulations are needed which take into account the higher temperatures and humidifies of these countries.
Oxidation may be promoted thermally, photolytically, or by chemical means. Compounds comprising aliphatic double bond systems are, in particular, sensitive towards degradation by oxidation, often via free-radical chain processes with molecular oxygen.
Such processes, known also as auto-oxidation, generally begins via an initiation process in which a free-radical is generated (e.g. via abstraction of a hydrogen atom by an initiator radical), followed by propagation steps involving oxygen and further compound molecules. Termination may occur when two radical products couple. Compounds comprising free-radical stabilizing aliphatic double bond configurations such as the methylene-interrupted polyene systems of polyunsaturated lipid derivatives are generally more susceptible to auto-oxidation. These and other oxidation processes can readily lead to, over time, the formation and accumulation of undesirable and pharmaceutically ineffective reaction products. Some of the degradants may be harmful or toxic.
The use of antioxidants and/or stabilizer excipients remains one of the foremost strategies for mitigating or preventing the oxidation of such compounds and to increase shelf-life. Typical antioxidants are butylated hydroxytoluene (BHT), ascorbic acid, tocopherol derivatives etc. Many antioxidants will act as free-radical scavengers; and act by terminating free-radicals and inhibiting the chain processes. Excipients which can act as metal ion chelators e.g. ethylene diamine tetraacetic acid (EDTA) may also be used to limit the effect of trace heavy metal impurities which can also catalyse oxidation reactions. The encapsulation or shielding of oxidation-sensitive compounds, such as with liposomes or cyclodextrins are also known methods of preventing degradation.
A further measure to prevent oxidative degradation of such compounds would be the removal of oxygen dissolved in the liquid vehicle through sparging with an inert gas, with for example, nitrogen. This is however process-intensive and not cost-effective, and requires, in addition, special attention during further processing steps and with packaging to prevent the reintroduction of atmosphere.
Polyunsaturated fatty acids (often abbreviated as PUFA) are a class of compounds that are prone to oxidative degradation. These include omega fatty acids such as omega-3 fatty acids (also known as (ω-3 fatty acids or n-3 fatty acids) and omega-6 fatty acids (also known as (ω-6 fatty acids or n-6 fatty acids). These are essential fatty acids because they are available only through dietary intake, and because they involved in many human metabolic processes and functions. As such, they have been implicated as beneficial in the treatment or prophylaxis of a wide variety of different health conditions.
For example, these compounds have been found to be useful for the topical treatment and prevention of ocular pathologies such as dry eye disease (DED). DED, also known as keratoconjunctivitis sicca or dysfunctional tear syndrome, is a multifunctional disorder of the tear film and ocular surface which results in discomfort, visual disturbance, and often even in ocular surface damage. The loss in dynamic stability of the structure, composition, volume and distribution, as well as clearance of the tear film can lead to the development of DED.
An inflammation cycle is one of the key processes that maintain and potentially progress the dry eye condition. Omega fatty acids, in relation to their anti-inflammatory properties, have been found to reduce the severity of DED and its symptoms and improve tear secretion. Omega-3 fatty acids, in particular, have been associated with the modulation of the production of anti-inflammatory and immunomodulatory eicosanoid prostaglandins such as PGE1. They are also implicated in suppressing the expression of pro-inflammatory cytokines such as IL-1 and TNF-α, which are associated with dry eye disease.
The formulation of such active ingredients prone to oxidation into topical ophthalmic compositions such as eye drops can however be challenging. The choices of excipients, and therefore antioxidants and stabilizers which can be used are more limited due to incompatibility, toxicity or poor tolerance with the ocular surface. At the same time, however, the minimization of degradation (resulting in colour changes of the preparation, precipitation of insoluble materials, etc.) becomes more acute.
Compositions comprising omega fatty acids for the topical treatment of the dry eye condition and its symptoms are however known in the art. Gastrointestinal intolerance resulting from the oral ingestion of large quantities of these fatty acids as supplements (and systemic absorption effect) can be avoided with direct and local administration of these active molecules to the surface of the eye.
For example, Remogen® Omega (marketed by TRB Chemedica International S.A.), is a commercially available ophthalmic preparation comprising omega fatty acids that indicated for dry eye conditions. As disclosed in its product information, the preparation is a hypotonic hydrogel containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), antioxidant vitamin E (tocopheryl acetate), the emollient substances carbopol 980, glycerol, pemulen, and sodium hydroxide, disodium phosphate, and distilled water. The hydrogel composition itself is described as a microemulsion, with a dispersion of the lipidic molecules (fatty acids and vitamin E). The product is packaged in the form of single-dose containers packed in an aluminium pouch, with the recommendation to discard the product immediately after use. With respect to stability, storage is suggested to be in a refrigerator at 2-8° C., with a shelf-life of 3 months if stored, at below 25° C., unrefrigerated. Due to its poor thermal stability, the product is shipped in a cold chain, i.e. transported in refrigerated containers and stored at the warehouse and in the pharmacy under refrigeration. Thus the consignment is expensive and requires a substantial effort in terms of temperature monitoring and logistics.
Similar, if not the same type of ophthalmic hydrogel compositions are also disclosed in U.S. 2012/0010280. It is described that the fatty acids are in solution in the antioxidant tocopheryl acetate, with the tocopheryl acetate present in amounts of up to 75% by weight of the oily mixture. These are dispersed as oily droplets in the hydrogel. Aqueous emulsions comprising a combination of omega-3 and omega-6 fatty acids, and surfactant (e.g. Tween 80), Glucam E-20, and a drop of vitamin E as an antioxidant were found to be poorly adapted for maintaining stability of the omega fatty acids are proposed in WO 2006/007510. It should be noted, however, that emulsion systems based on hydrogels, with their generally increased viscosity and bioadhesive properties may incur, upon instillation and also during its contact time to the ocular surface, irritating foreign body sensation and blurred vision. Depending also on the degree of their viscosity, these may be more difficult to dispense and administer.
In general, one of the major disadvantages of formulations based on emulsions system is that in contrast to single phase systems, emulsion systems may be more complex and difficult to manufacture, especially in sterile form. Frequently, they are not readily sterilisable by thermal treatment without negative impact on their physical properties. Emulsions are also inherently unstable, and could phase separate with time or fluctuations in storage conditions. They, as with all aqueous based systems, are more prone to microbial contamination during use as well. The aseptic processing of emulsions is complex, costly, and is associated with higher risks of failure, i.e. microbial contamination.
Retinoid (Vitamin A) derivatives are another class of hydrocarbon compounds comprising high levels of polyunsaturation, and which are also prone to degradation via oxidation pathways. Retinoid derivatives include retinol, retinal, retinoic acid, tretinoin, isotretinoin, alitretinoin, and related derivatives. Vitamin A derivatives have been used for the treatment of inflammation in relation to the cornea, conjunctiva and other mucosal and epithelial tissues, including conditions such as dry eye disease.
U.S. 2012/0095097 for example discloses aqueous ophthalmic compositions comprising Vitamin A, at least 0.4 w/v % of polyoxyethylene polypropylene glycol and trometamol. Antioxidants such as dibutylhydroxytoluene and α-tocopherol acetate, may also be present in these compositions. These compositions are based on micelles of Vitamin A, which is presumably shielded and stabilized by non-ionic surfactant polyoxyethylene polypropylene glycol. These compositions are not preserved as such.
In principle, these preparations would require, if they were to be presented in multi-dose containers which are in principle more cost-efficient and convenient for patients than single-use vials, preservation in order to ensure their microbiological quality. The same would be applicable to all aqueous-based preparations. At the same time however, preservatives which can be used in ophthalmic formulations are potentially damaging to the eye, in particular to the ocular surface, and should be avoided especially in the context of dry eye disease. At least in earlier years, multi-dose formulations for ophthalmic administration had to be preserved using a physiologically acceptable preservative in order to reduce the risk of microbial contamination and infection.
Most preservatives are however problematic for DED patients in that they have a potential to negatively affect the ocular surface, thus counteracting the therapeutic intent. This is particularly relevant for patients with moderate to severe dry eye disease symptoms who may require frequent use for symptom relief, as well as patients who require multiple preserved topical medicaments.
As an alternative, single-dose containers are the main option for the administration of non-preserved formulations such as those used for the Remogen® Omega product. These are however less cost-efficient and convenient to handle for the patient than the conventional multi-dose bottle. Whilst ophthalmic formulations utilizing ‘vanishing’ preservatives such as sodium chlorite or sodium perborate, which can convert to non-toxic ions and water after instillation and contact with the tear film may also be an option, these may still be irritating to patients especially those with severe disease who may not have sufficient tear volume to effectively degrade the preservatives.
WO 2011/073134 discloses ophthalmic topical pharmaceutical compositions comprising immunosuppressant macrolides such as ciclosporin A and semifluorinated alkanes, for treatment of keratoconjunctivitis sicca. The semifluorinated alkanes in the disclosed compositions serve as suitable liquid vehicles for delivering the therapeutic pharmaceutical agent to the eye, and in particular have a high capacity for dissolving extremely challenging poorly soluble compounds such as ciclosporin. However, there is no mention of the ability of semifluorinated alkanes to stabilize oxidation-sensitive compounds over an extended period of time.
It is therefore an object of the present invention to provide a novel composition which comprising one or more active compounds comprising more than one aliphatic double prone to oxidation, and which at the same time addresses and overcomes the various issues and at least one of the limitations or disadvantages associated with prior art formulations. In a specific aspect, it is an object of the invention to provide an ophthalmic composition for the treatment or prevention of a condition or disease such as dry eye or conditions relating to the inflammation of the ocular tissue. In a further aspect, it is an object of the invention to provide a method of stabilizing an active compound with more than one aliphatic double bond prone to oxidation which does not exhibit one or more of the disadvantages of prior art. Further objects of the invention will become clear on the basis of the following description, examples, and patent claims.